16.    Antioxidants combined with Nebivolol improves hemodynamic parameters in a                     model of metabolic syndrome

Diagnosis of Metabolic syndrome relies on the presence of at least three alterations among visceral obesity, hypertension, dyslipidemia, and glycemic alterations. These multiple risk factors accelerate the development of cardiovascular diseases in a cooperative way. The imbalance between reactive oxygen species (ROS) and nitric
oxide (NO) has been implicated in the pathogenesis of hypertension due to, at least in part, a reduction in Glutathione (GSH). The model of hypertension by oral fructose overload occurs with endothelial dysfunction. Nebivolol is a third generation β-blocker with antioxidant effects which enhances the availability of NO, by
increasing the expression of eNOS via the activation of the β3 receptor. Taking into account the role of oxidative stress on the development of hypertension, the aim of this work was to assess the effects of antioxidants -tempol or N-acetylcysteine- in combination with Nebivolol, on systolic blood pressure (SBP), echocardiography parameters and vascular relaxation. Male Sprague Dawley rats (SDR) (250-300g), treated with or without fructose (10% w/v) in tap water for 12 weeks, were distributed in 5 groups (n=6): control (C), fructose (F), fructose plus nebivolol (15 mg/kg/day) (FN), or in combination with tempol (60 mg/Kg/day) (FNT) and nebivolol plus N-acetylcisteine (10 mg/kg/day) (FNNAC). The indirect SBP was measured by tail-cuff method. The vascular relaxation was measured in aortic rings using organ bath. At the end of the treatment, echocardiographic evaluation was performed. In comparison with normotensive rats, fructose overloaded rats showed an increase of SBP (mmHg, C: 120±2 vs F: 138±4, p<0.05). Treatment with nebivolol, alone (116±1.20 mmHg) or combined with antioxidants (mmHg, FNT: 118±2.8; FNNAC: 110±2 vs F, p<0.05), was able to reduce SBP when compared with fructose rats. The echocardiographic parameters were improved by the combination of nebivolol with tempol.The Isovolumetric relaxation time was improved by nebivolol and the combination with tempol therapy (msec, FN: 25,6 ± 0,5; FNT: 24,8 ± 0,8 vs F: 29,5 ± 2,6; p<0.05), while the ejection fraction was improved only by the combination with tempol therapy (%, FNT: 72 ± 13 vs F: 67 9± 3; p<0.05). In the same way fractional shortening was improved in fructose rats treated with nebivolol plus tempol (%, FNT: 34,90±1,11 vs F: 29,50±2,60; p<0,05).On the other hand, the vascular relaxation was improved with the combination of nebivolol plus N-acetylcysteine administration In conclusion, nebivolol prevents the increase of Systolic blood pressure induced by fructose overload. The combination with antioxidants -tempol or N-acetylcysteineplus
nebivolol improves vascular relaxation and echocardiographic parameters.